"When a case proves too baffling for the minds of Interpol, they turn to the talents of Department S."; from the ITC trailer for the series.

The series was created by Dennis Spooner and Monty Berman, although neither wrote any of the episodes, which were instead scripted by ITC regulars such as Terry Nation and Philip Broadley. Many of the directors on the show had also worked on other ITC shows such as The Saint, Danger Man and Randall and Hopkirk (Deceased).

The series was shot on 35mm film and designed, like all ITC's film productions, to fit the United States commercial format. Although episodes begin with a cold open (after the 'S' logo is shown), unusually, the episode title, writer and director credits appear on screen before the opening title sequence, though after the theme tune has started. With a few exceptions, the principal cast is always studio-bound. Some exteriors are represented by studio buildings, while the rest are mainly shown in second-unit footage using doubles where necessary. Outside locations were, in common with similar series, largely restricted to the Hertfordshire countryside in the vicinity of Borehamwood. At least one foreign location was used, featuring Peter Wyngarde on the streets of Vienna. Otherwise, foreign locations are usually established by the use of stock footage.

Department S is a division of Interpol headed by international bureaucrat Sir Curtis Seretse (Dennis Alaba Peters). Its headquarters is in Paris and its members investigate international cases that other crime agencies cannot solve.

The team itself is led by American and former FBI agent Stewart Sullivan (Joel Fabiani), who takes direction from Seretse. Outside of his FBI experience, little is known about Stewart except that he is pragmatic and hands-on, and does much of the leg-work, confronting the criminals.

Jason King (Peter Wyngarde) is the ideas man, but also helps in the field. He is an adventure novelist who uses details from their cases to write his novels. The living he makes writing novels affords him a hedonistic lifestyle, and he is often seen with "beautiful" women though he has no permanent love interest in the series; in one episode he mentions he is a widower whose wife was killed in a plane crash. Jason King also serves as comic relief in the series, especially in scenes of hand-to-hand combat where he winds up being subdued as often as he prevails.

Annabelle Hurst (Rosemary Nicols) is a computer expert and analyst as well as a field investigator. She sometimes appears in seductive, glamorous disguises, and is shown in her underwear in the first episode. There are ongoing hints of romantic interest between Stewart and Annabelle during the series.